The overall aim of the P.I.'s research is to better understand gender differences in energy and nutrient metabolism that related to the development and/or protection against disease. The health risks associated with a number of diseases including obesity and coronary heart disease are different between males and females. Knowledge of gender differences in energy and nutrient metabolism are required to fully understand the metabolic basis of these diseases. Studies in this proposal will begin to determine gender specific aspects of energy and nutrient metabolism and how these change at menopause. Specific aim number 1 will be to determine the sources of carbohydrate and lipid fuels utilized during exercise in males and females. This will be determined using indirect calorimetry and stable isotope techniques and muscle biopsies. Specific aim number 2 will be to determine the lipolytic response to catecholamines in males and females by using the pancreatic clamp technique in conjunction with catecholamine infusions and stable isotope measurements. Specific aim number 3 will be to determine whether males and females differ in their ability to remove exogenous lipid from the circulation and whether there are gender differences in the ability of insulin to suppress endogenous very-low density lipoprotein triglyceride (VLDL-TG) production. Triglyceride removal will be assessed in response to an intravenous fat tolerance test. Relative changes in VLDL-TG production will be measured following the radioactive labeling of VLDL-TG and measurement of VLDL-TG kinetics under basal and hyperinsulinemic/euglycemic conditions. Specific aim number 4 will be to determine the effect of menopause and hormone replacement therapy on energy expenditure and resting substrate utilization. Free-living energy expenditure will be measured using the doubly labelled water technique and substrate utilization will be assessed using indirect calorimetry and stable isotope techniques. These studies will further our understanding of the metabolic basis for disease risk in males and females.